C h a p t e r 4
Cell Proliferation and Tissue Regeneration and Repair
77
There is continued interest in developing growth factors
as a means of increasing cell proliferation and enhanc-
ing wound healing as well as developing strategies to
block growth factor signaling pathways that could be
used to inhibit malignant cell proliferation in cancer.
Extracellular Matrix and Cell–Matrix
Interactions
The understanding of tissue regeneration and repair has
expanded over the past several decades to encompass the
complex environment of the ECM. There are two basic
forms of ECM: (1) the
basement membrane,
which sur-
rounds epithelial, endothelial, and smooth muscle cells;
and (2) the
interstitial matrix,
which is present in the
spaces between cells in connective tissue and between
the epithelium and supporting cells of blood vessels.
The ECM is secreted locally and assembles into a net-
work of spaces surrounding tissue cells (see Chapter 1).
There are three basic components of the ECM: fibrous
structural proteins (e.g., collagen and elastin fibers),
water-hydrated gels (e.g., proteoglycans and hyaluronic
acid) that permit resilience and lubrication, and adhe-
sive glycoproteins (e.g., fibronectin, laminin) that con-
nect the matrix elements to one another and to cells
1–3,9
(Fig. 4-3). Integrins are a family of transmembrane gly-
coproteins that are the main cellular receptors for ECM
components such as fibronectin and laminin. They bind
to many ECM components, initiating signaling cas-
cades that affect cell proliferation and differentiation.
Fibroblasts, which reside in close proximity to collagen
fibers, are responsible for the synthesis of collagen, elas-
tic, and reticular fibers, and complex carbohydrates in
the ground substance.
The ECM provides turgor to soft tissue and rigidity
to bone; it supplies the substratum for cell adhesion; it
is involved in the regulation of growth, movement, and
differentiation of the cells surrounding it; and it provides
for the storage and presentation of regulatory molecules
that control the repair process. The ECM also provides
the scaffolding for tissue renewal. Although the cells in
many tissues are capable of regeneration, injury does
not always result in restoration of normal structure
unless the ECM is intact. The integrity of the underly-
ing basement membrane, in particular, is critical to the
regeneration of tissue. When the basement membrane is
disrupted, cells proliferate in a haphazard way, resulting
in disorganized and nonfunctional tissues.
Critical to the process of wound healing are transi-
tions in the composition of the ECM. In the transitional
process, the ECM components are degraded by prote-
ases (enzymes) that are secreted locally by a variety of
cells (fibroblasts, macrophages, neutrophils, synovial
cells, and epithelial cells). Some of the proteases, such
as the collagenases, are highly specific, cleaving particu-
lar proteins at a small number of sites.
10,11
This allows
for the structural integrity of the ECM to be retained
while healing occurs. Because of their potential to pro-
duce havoc in tissues, the actions of the proteases are
tightly controlled. They are typically produced in an
inactive form that must first be activated by certain
chemicals likely to be present at the site of injury, and
they are rapidly inactivated by tissue inhibitors. Recent
research has focused on the unregulated action of the
proteases in disorders such as cartilage matrix break-
down in arthritis and neuroinflammation in multiple
sclerosis.
11
Cell
membrane
Integrin
Proteoglycan
Hyaluronic
acid
Collagen
Fibronectin
Fibroblast
FIGURE 4-3.
Components of the extracellular matrix and
supporting connective tissue components involved in tissue
repair.
SUMMARY CONCEPTS
■■
The process of tissue growth and repair involves
proliferation of functioning parenchymal cells
of an organ or body part and its supporting
connective tissues and extracellular matrix.
■■
Cell proliferation refers to the process of
increasing cell numbers by mitotic division.
Cell differentiation is the process whereby
a cell becomes more specialized in terms of
structure and function.The periodic biochemical
and structural events occurring during cell
proliferation are called the cell cycle.
■■
Body cells are divided into types according to
their ability to regenerate. Labile cells, such as
the epithelial cells of the skin and gastrointestinal
tract, are those that continue to regenerate
throughout life. Stable cells, such as those in the
liver, are those that normally do not divide but are
capable of regeneration when confronted with an
appropriate stimulus. Permanent or fixed cells are
(continued)
